Stromal miR-20a controls paracrine CXCL8 secretion in colitis and colon cancer
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Steven A. Signs1, Robert C. Fisher1, Uyen Tran2, Susmita Chakrabarti3, Samaneh K. Sarvestani1, Shao Xiang1, David Liska1,4, Veronique Roche1, Wei Lai1, Haley R. Gittleman5, Oliver Wessely2,* and Emina H. Huang1,4,*
1Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
2Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
3Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
4Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio, USA
5Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio USA
Emina H. Huang, email: [email protected]
Keywords: fibroblasts; miR-20a; CXCL8; colitis; colon cancer
Abbreviations: CAC: colitis-associated cancer; IBD: inflammatory bowel disease; UC: ulcerative colitis
Received: November 30, 2017 Accepted: February 10, 2018 Published: February 14, 2018
Inflammatory bowel disease (IBD) affects one million people in the US. Ulcerative colitis (UC) is a subtype of IBD that can lead to colitis-associated cancer (CAC). In UC, the rate of CAC is 3-5-fold greater than the rate of sporadic colorectal cancer (CRC). The pathogenesis of UC and CAC are due to aberrant interactions between host immune system and microenvironment, but precise mechanisms are still unknown. In colitis and CAC, microenvironmental fibroblasts exhibit an activated, inflammatory phenotype that contributes to tumorigenesis accompanied by excessive secretion of the chemokine CXCL8. However, mechanisms regulating CXCL8 secretion are unclear. Since it is known that miRNAs regulate chemokines such as CXCL8, we queried a microRNA library for mimics affecting CXCL8 secretion. Among the identified microRNAs, miR-20a/b was further investigated as its stromal expression levels inversely correlated with the amounts of CXCL8 secreted and predicted fibroblast tumor-promoting activity. Indeed, miR-20a directly bound to the 3′UTR of CXCL8 mRNA and regulated its expression by translational repression. In vivo co-inoculation studies with CRC stem cells demonstrated that fibroblasts characterized by high miR-20a expression had reduced tumor-promoting activities. These studies reveal that in stromal fibroblasts, miR-20a modulates CXCL8 function, therefore influencing tumor latency.
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